Ticagrelor effectively and reversibly blocks murine platelet P2Y12-mediated thrombosis and demonstrates a requirement for sustained P2Y12 inhibition to prevent subsequent neointima.

OBJECTIVE: Our goal was to study the effects of ticagrelor on murine platelet function and thrombosis and characterize the time course of P2Y(12) inhibition required to inhibit neointima formation following vascular injury. METHODS AND RESULTS: Mice were treated with ticagrelor or vehicle. Platelet aggregation and P-selectin expression were assessed over time, and thrombus formation was assessed in laser-injured cremasteric arterioles of P2Y(12)+/+ and P2Y(12)-/- mice. Neointima formation in FeCl(3)-injured carotid artery was assessed in C57BL/6 mice treated with different regimens of ticagrelor. Ticagrelor inhibited platelet aggregation and P-selectin expression in a dose-dependent, reversible manner. Ticagrelor inhibited thrombus formation to the same extent as seen in P2Y(12)-/- mice. Neointima formation was markedly reduced in mice treated with ticagrelor before and 4 hours after injury (neointima area: control, 39 921±22 749 µm(2), versus ticagrelor, 3705±2600 µm(2); P<0.01), whereas administration of ticagrelor either before injury only or from 4 hours postinjury was ineffective. CONCLUSIONS: Ticagrelor effectively and reversibly inhibits P2Y(12)-mediated platelet function and thrombosis in mice. P2Y(12) inhibition is required both at the time of and after injury to effectively inhibit neointima formation. Additional studies are warranted to evaluate the role of P2Y(12) inhibition in preventing restenosis.

Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy.

OBJECTIVES: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy aimed to compare the antiplatelet effects of clopidogrel and ticagrelor in patients with acute coronary syndromes. BACKGROUND: The PLATO study demonstrated superiority of ticagrelor over clopidogrel in the prevention of ischemic events in patients with acute coronary syndromes. METHODS: Patients were randomized to receive either clopidogrel (300- to 600-mg loading dose [LD], 75 mg/day) or ticagrelor (180-mg LD, 90 mg twice daily). The effects of maintenance therapy were studied in 69 patients pre- and 2 to 4 h post-dose after at least 28 days. The LD effect was studied in 24 clopidogrel-naive patients. Light transmittance aggregometry (adenosine diphosphate 5 to 20 µM), VerifyNow P2Y12, and VASP phosphorylation assays were performed. RESULTS: During maintenance therapy, ticagrelor achieved greater suppression of platelet reactivity compared with clopidogrel. The mean maximum light transmittance aggregometry responses (adenosine diphosphate 20 µM) post-maintenance dose were 44±15% for clopidogrel and 28±10% for ticagrelor (p<0.001). High platelet reactivity was seen more frequently in the clopidogrel group. Proton pump inhibitor use was associated with higher platelet reactivity with clopidogrel but not ticagrelor. The ticagrelor LD also achieved greater inhibition of platelet aggregation compared with the clopidogrel LD. CONCLUSIONS: Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy.

Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study.

OBJECTIVES: We prospectively assessed cardiac and pulmonary function in patients with stable coronary artery disease (CAD) treated with ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease) study. BACKGROUND: Ticagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes. Dyspnea develops in some patients treated with ticagrelor, and it is not known whether this is associated with changes in cardiac or pulmonary function. METHODS: In all, 123 stable aspirin-treated CAD patients randomly received either ticagrelor (180 mg load, then 90 mg twice daily; n=57), clopidogrel (600 mg load, then 75 mg daily; n=54), or placebo (n=12) for 6 weeks in a double-blind, double-dummy design. Electrocardiography, echocardiography, serum N-terminal pro-brain natriuretic peptide, and pulmonary function tests were performed before (baseline) and 6 weeks after drug administration and/or after development of dyspnea. RESULTS: After drug administration, dyspnea was reported by 38.6%, 9.3%, and 8.3% of patients in the ticagrelor, clopidogrel, and placebo groups, respectively (p<0.001). Most instances were mild and/or lasted<24 h, although 3 patients discontinued ticagrelor because of dyspnea. Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, and in ticagrelor-treated patients with dyspnea, there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters. CONCLUSIONS: Dyspnea is commonly associated with ticagrelor therapy, but was not associated in this study with any adverse change in cardiac or pulmonary function. (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ONSET/OFFSET]; NCT00528411).

Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.

BACKGROUND: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. METHODS AND RESULTS: In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 micromol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P<0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved >50% IPA (98% versus 31%, P<0.0001) and >70% IPA (90% versus 16%, P<0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72-hour slope [% IPA/h] -1.04 versus -0.48, P<0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS). CONCLUSIONS: Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation.